The objective of this proposal is to determine the effect of diabetes on endoneural blood flow (EBF), motor nerve conduction velocity (MNCV) and vasorelaxation of arteriole branches that supply circulation to the sciatic nerve. Since nerve ischemia is a primary factor in the development of diabetic neuropathy (DN), understanding the effect of diabetes on the vascular responsiveness of blood vessels that supply neural tissue is important. The long-rang goal of my laboratory has been to identify the diabetes-induced defects that contribute to the development of DN. Consequently, others and we have shown that slowing in MNCV is accompanied by a reduction in EBF. The etiology of these abnormalities is not well understood and has been attributed to a variety of defects affective nerve and vascular tissue. Because of the multiple abnormalities is not well understood and has been attributed to a variety of defects affecting nerve and vascular tissue. Because of the multiple abnormalities contributing to DN it is impractical to treat this disease by correcting each of them. Therefore, investigators are faced with the problem of determining which vascular or metabolic related defects have the greatest impact on the clinical features of DN and then design strategies to treat the more clinically relevant defects. We have shown that vascular relaxation of arterioles that supply circulation to the sciatic nerve is impaired by diabetes and, in this proposal, will test the hypothesis that the origin of the vascular defects, and thus a major cause of DN, is an impairment in the regulation of vascular tone mediated by nitric oxide (NO) and arachidonic acid metabolites. We propose that combining alpha-lipoic acid (an antioxidant) and/or evening primrose oil (a natural source of gamma-linolenic acid) treatment will correct the vascular defects and improve EBV and MNCV. The specific objectives of this proposal are: 1) Determine if treating streptozotoxin- induced diabetic rats with alpha-lipoic acid and/or evening primrose oil prevents diabetes-induced impairment in vascular relaxation in arterioles that provide circulation to the sciatic nerve, the reduction in EBV and slowing of MNCV, 2) Determine whether exogenous treatment of arterioles with L-arginine, superoxide dismutase (SOD) with and without catalase, or arachidonic acid, improves the diabetes-induced defect in endothelium- dependent vasorelaxation, and 3) determine whether exogenous treatment of arterioles with adenoviruses containing endothelial nitric oxide synthase (eNOS), superoxide dismutase (SOD) with and without catalase or delta-6 desaturase prevents the diabetes-induced defect in endothelium-dependent vasorelaxation. In summary, these studies will provide us with a better understanding of the etiology of DN and improved treatments for preventing the diabetes-induced changes in vascular and neural function.